Myotonic Dystrophy is associated with a variable length expansion of a trinucleotide (CTG) segment with in the 3' untranslated region of the DM-kinase gene. The mutant allele of the DM kinase gene produces poly(A)-plus RNA at a much lower level (20-25%) than that seen with the normal allele in the same biopsies. the CTG expansion found in the mutant allele could therefore affect either (a) the site of transcription termination and influence the expression and polyadenylation of the DM-kinase or neighboring genes or (b) nuclear processing of the primary transcript containing the CTG- repeats. either of these effects may occur only in muscle cells or be more generalized in some individuals, accounting for the variable phenotypes associated with the disease. In order to test these hypotheses we set up a model system in which the CTG- repeats are placed in a heterologous gene and have observed their direct effect on gene expression. We propose to follow up on these preliminary studies and extend them to understand the molecular pathophysiology of the disease and gain possible insight into diagnosis and therapeutics. Aim 1 is to further test the hypothesis that the defects seen in DM kinase RNA metabolism are a direct result of the CTG-expansion and not due to some other genetic modifiers which have yet to be mapped in the patients. Aim 2 is to test the hypothesis that the CTG-repeats cause transcription termination by measuring transcription beyond the repeats and the normal end point of the gene. Aim 3 is to test the hypothesis that the CTG-repeats influence nuclear retention and/or mRNA stability. Aim 4 is to test the hypothesis that the CTG-repeats inhibit polyadenylation. The results from these experiments should have implications for understanding expansion disorders and should provide information on normal muscle mRNA metabolism by identifying defect(s) in the process. the results may provide information enabling better prognostic diagnoses of patients and/or elucidate novel avenues for molecular therapeutics.